High and Persistent Anti-GM1 Antibody Titers Are Associated With Poor Clinical Recovery in Guillain-Barré Syndrome.

BACKGROUND AND OBJECTIVES: Guillain-Barré syndrome (GBS) is an acute immune-mediated polyradiculoneuropathy that may follow a preceding infection inducing a cross-reactive antibody response to glycosphingolipids in peripheral nerves. The immune response in GBS is considered to be short lasting, explaining its monophasic clinical course. However, the disease course varies between patients, and residual deficits frequently occur. The duration of the antibody response has not been defined extensively in GBS, and the persistence of these antibodies may impair clinical recovery. The aim of this study was to determine the titer course of serum antibody titers to the ganglioside GM1 in relation to clinical course and outcome in patients with GBS. METHODS: Acute-phase sera from patients with GBS included in previous therapeutic trials were screened for anti-GM1 IgG and IgM antibodies in ELISA. Anti-GM1 antibody titers were determined in sera collected at entry and during a 6-month follow-up. Clinical course and outcomes were compared between groups based on the titer course. RESULTS: Anti-GM1 antibodies were detected in 78 (20.7%) of 377 included patients. The anti-GM1 IgG and IgM antibody titer course was highly variable between patients. A subset of anti-GM1-positive patients had persistent anti-GM1 antibodies at 3 months (n = 27/43 [62.8%]) and 6 months (n = 19/41 [46.3%]). Patients with a high anti-GM1 IgG and IgM titer at entry recovered more slowly and less complete than anti-GM1-negative patients (IgG: p = 0.015, IgM: p = 0.03). High vs low IgG titers were independently associated with poor outcome after correcting for known prognostic factors (p = 0.046). Among patients with a high anti-GM1 IgG titer at entry, a slow titer decline was associated with poor outcome at 4 weeks (p = 0.003) and 6 months (p = 0.032). Persistent high IgG titers at 3 and 6 months were associated with poor outcome at 6 months (3 months: p = 0.022, 6 months: p = 0.004). DISCUSSION: High anti-GM1 IgG and IgM antibody titers at entry and persistent high anti-GM1 IgG antibody titers are associated with poor outcome in patients with GBS. Antibody persistency indicates ongoing antibody production long after the acute disease state in GBS. Further research is required to determine whether antibody persistency interferes with nerve recovery and is a target for treatments.

Genetic biomarkers for intravenous immunoglobulin response in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a clinical and electrophysiological heterogeneous immune-mediated polyneuropathy. Intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange are proven effective treatments for CIDP. The clinical response to IVIg is variable between patients and currently unexplained. Finding biomarkers related to treatment response can help to understand the diversity of CIDP and personalise treatment choice. METHODS: We investigated whether genetic variation between patients may explain some of these differences in treatment response. Based on previous publications, we selected six candidate genes that might affect immune and axonal functions, IVIg metabolism, and treatment response in CIDP. Genetic variants were assessed in 172 CIDP patients treated with at least one course of IVIg (2 g/kg). A response to IVIg was defined by ≥1 grade improvement on the modified Rankin Scale. Blood samples were tested for variations in CNTN2, PRF1, FCGRT, FCGR2B, GJB1, and SH2D2A genes. RESULTS: In univariate analysis, patients with the FCGR2B promoter variant 2B.4/2B.1 responded more often to IVIg than patients with the 2B.1/2B.1 variant (odds ratio [OR] = 6.9, 95% confidence interval [CI] = 1.6-30; p = 0.003). Patients with the p.(Ala91Val) variant of PRF1 were less often IVIg responsive (OR = 0.34, 95% CI = 0.13-0.91; p = 0.038). In multivariate analysis, both PRF1 and FCGR2B showed discriminative ability to predict the chance of IVIg response (area under the curve = 0.67). CONCLUSIONS: Variations in PRF1 and the promoter region of FCGR2B are associated with the response to IVIg in CIDP. These findings, which require validation, are a first step towards the understanding of the heterogeneity in the treatment response in CIDP.

IVIg-induced plasmablasts in patients with Guillain-Barré syndrome.

Objective: The Guillain-Barré syndrome (GBS) is an acute, immune-mediated disease of peripheral nerves. Plasmablasts and plasma cells play a central role in GBS by producing neurotoxic antibodies. The standard treatment for GBS is high-dose intravenous immunoglobulins (IVIg), however the working mechanism is unknown and the response to treatment is highly variable. We aimed to determine whether IVIg changes the frequency of B-cell subsets in patients with GBS. Methods: Peripheral blood mononuclear cells were isolated from 67 patients with GBS before and/or 1, 2, 4, and 12 weeks after treatment with high-dose IVIg. B-cell subset frequencies were determined by flow cytometry and related to serum immunoglobulin levels. Immunoglobulin transcripts before and after IVIg treatment were examined by next-generation sequencing. Antiglycolipid antibodies were determined by ELISA. Results: Patients treated with IVIg demonstrated a strong increase in plasmablasts, which peaked 1 week after treatment. Flow cytometry identified a relative increase in IgG2 plasmablasts posttreatment. Within IGG sequences, dominant clones were identified which were also IGG2 and had different immunoglobulin sequences compared to pretreatment samples. High plasmablast frequencies after treatment correlated with an increase in serum IgG and IgM, suggesting endogenous production. Patients with a high number of plasmablasts started to improve earlier (P = 0.015) and were treated with a higher dose of IVIg. Interpretation: High-dose IVIg treatment alters the distribution of B-cell subsets in the peripheral blood of GBS patients, suggesting de novo (oligo-)clonal B-cell activation. Very high numbers of plasmablasts after IVIg therapy may be a potential biomarker for fast clinical recovery.

Neonatal Fc receptor promoter gene polymorphism does not predict pharmacokinetics of IVIg or the clinical course of GBS.

Treatment of Guillain-Barré syndrome with a standard course of high-dose intravenous immunoglobulin (IVIg) results in a variable clinical recovery which is associated with changes in serum IgG levels after treatment. The neonatal Fc-receptor protects IgG from degradation, and a genetic polymorphism in its promoter region that influences the expression of Fc-receptor, may in part explain the variation in IgG levels and outcome. This polymorphism was determined by polymerase chain reaction in a cohort of 257 patients with Guillain-Barré syndrome treated with IVIg. We could not demonstrate a relation between this polymorphism, the pharmacokinetics of IVIg, or the clinical course and outcome.

Innate Immunity to Campylobacter jejuni in Guillain-Barré Syndrome.

OBJECTIVE: Guillain-Barré syndrome (GBS) is a postinfectious neuropathy most frequently caused by Campylobacter jejuni. Lipo-oligosaccharides (LOS), expressed by C. jejuni induce antibodies that cross-react with self-glycolipids in peripheral nerves, causing neuropathy. Less than 1 in 1,000 persons infected with C. jejuni develop GBS, and the factors that determine GBS susceptibility are poorly understood. We hypothesized that these persons have a high intrinsic dendritic cell (DC) response to C. jejuni LOS through Toll-like receptor 4 (TLR4) activation. METHODS: Intrinsic DC responsiveness to C. jejuni LOS was investigated first in 20 healthy controls at three time points with a 3-month interval, and second in patients, who previously developed GBS after a C. jejuni infection (n = 27) and controls (n = 26). RESULTS: The DC response to C. jejuni LOS was highly variable between, but not within, healthy individuals, suggesting that intrinsic factors determine the magnitude of TLR4-mediated innate response. High responsiveness to C. jejuni LOS by former GBS patients was evidenced by increased expression of CD38 and CD40. Frequency of CD38, CD40 and type I interferon high responders was significantly increased in the GBS group. INTERPRETATION: These results suggest that a strong response to TLR4 stimulation is a critical host condition for the development of GBS after an infection with C. jejuni.

IgG Fc N-glycosylation in Guillain-Barré syndrome treated with immunoglobulins.

Intravenous immunoglobulin (IVIg) is the treatment of choice for Guillain-Barré syndrome (GBS), an immune-mediated peripheral neuropathy causing rapidly progressive limb weakness and respiratory failure. The working mechanism of IVIg in autoimmune diseases has not been elucidated, but previous studies indicate that some anti-inflammatory effects may be mediated by the N-glycosylation of the Fc-portion of IgG. GBS is a model disease to investigate these effects because GBS is an acute and monophasic disorder usually affecting healthy persons, which is treated with a standard course of IVIg, although the clinical response is highly variable. In the current study, the N-glycosylation of the Fc-portion of serum IgG was investigated in patients with GBS before and after treatment with IVIg in relation to clinical course and outcome. Glycoforms of serum IgG1 and IgG2 were determined separately by liquid chromatography mass spectrometry. These IgG subclasses were purified from the serum of 174 GBS patients before and in 150 patients 2 weeks after standard IVIg treatment regimen. Treatment-naive GBS patients compared with age- and sex-matched controls had lower levels of galactosylation of IgG1 and IgG2. IVIg preparations contained relatively high levels of galactosylated and sialylated IgG Fc glycoforms compared with serum IgG in patients. Treatment with IVIg resulted in an increase in serum of the Fc-galactosylation and -sialylation of both IgG1 and IgG2. The extent of normalization in serum IgG Fc glycosylation varied between patients. Multiple logistic regression analysis showed that patients with persistent low IgG galactosylation and sialylation despite IVIg treatment had the most severe forms of GBS and needed ventilator support more often. Kaplan-Meier analysis showed that these patients also needed more time to be able to walk again compared with patients with a normalized IgG Fc glycosylation profile. In conclusion, our results suggest that serum IgG Fc glycosylation in GBS is related to disease severity and clinical recovery after IVIg and may help to develop new measures to monitor the efficacy of treatment.

Sialylation of Campylobacter jejuni endotoxin promotes dendritic cell-mediated B cell responses through CD14-dependent production of IFN-ß and TNF-α.

Campylobacter jejuni is the most common bacterial cause of human gastroenteritis and often precedes development of Guillain-Barré syndrome (GBS), a life-threatening paralytic disease. The incorporation of the carbohydrate sialic acid into C. jejuni lipooligosaccharides (LOS) is associated with increased severity of gastroenteritis and with induction of GBS; however, the underlying mechanisms remain completely unknown. In this study, we demonstrate that sialic acids in C. jejuni endotoxin enhance the rapid production of IFN-ß and TNF-α by human dendritic cells (DCs). Using neutralizing Abs and receptors it was shown that these DC-derived cytokines promote the proliferation of human mucosal B cells in a T cell-independent manner. The production of both IFN-ß and TNF-α by DCs in response to LOS requires CD14, and the amplified response of DCs to sialylated C. jejuni LOS is CD14 dependent. Together, these results indicate that sialylation of C. jejuni LOS increases DC activation and promotes subsequent B cell responses through CD14-driven production of IFN-ß and TNF-α. This enhanced DC/B cell response may explain the increased pathogenicity of sialylated C. jejuni and may be key to the initiation of B cell-mediated autoimmunity in GBS.

Serum IgG levels in IV immunoglobulin treated chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: To determine the variability of serum IgG in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: All 25 CIDP patients had active but stable disease and were treated with individually optimised fixed dose IVIg regimens. IgG was measured by turbidimetry and variability was defined as coefficient of variation (CV). RESULTS: The intra-patient variability of the pre-treatment IgG levels, post-treatment levels and increase in serum IgG shortly after IVIg (ΔIgG) was low (mean CV=3%, 4%, 10%). The inter-patient variability between patients treated with the same dose and interval was low in pre-treatment, post-treatment and ΔIgG level (mean CV=13%, 11%, 20%). The ΔIgG levels were associated with IVIg dosage (rs=0.78, p<0.001). CONCLUSIONS: Clinically stable CIDP patients show a steady-state in serum IgG after serial IVIg infusions. The low intra- and inter-patient variability in IgG may indicate that constant levels are required to reach this stability.

Guillain-Barré syndrome-related Campylobacter jejuni in Bangladesh: ganglioside mimicry and cross-reactive antibodies.

BACKGROUND: Campylobacter jejuni is the predominant antecedent infection in Guillain-Barré syndrome (GBS). Molecular mimicry and cross-reactive immune responses to C. jejuni lipo-oligosaccharides (LOS) precipitate the development of GBS, although this mechanism has not been established in patients from developing countries. We determined the carbohydrate mimicry between C. jejuni LOS and gangliosides, and the cross-reactive antibody response in patients with GBS in Bangladesh. METHODOLOGY: Sera from 97 GBS patients, and 120 neurological and family controls were tested for antibody reactivity against LOS from C. jejuni isolates from GBS patients in Bangladesh (BD-07, BD-39, BD-10, BD-67 and BD-94) by enzyme-linked immunosorbent assay (ELISA). Cross-reactivity to LOS was determined by ELISA. The LOS outer core structures of C. jejuni strains associated with GBS/MFS were determined by mass spectrometry. PRINCIPLE FINDINGS: IgG antibodies to LOS from C. jejuni BD-07, BD-39, BD-10, and BD-67 IgG antibodies were found in serum from 56%, 58%, 14% and 15% of GBS patients respectively, as compared to very low frequency (<3%) in controls (p<0.001). Monoclonal antibodies specific for GM1 and GD1a reacted strongly with LOS from the C. jejuni strains (BD-07 and BD-39). Mass spectrometry analysis confirmed the presence of GM1 and GD1a carbohydrate mimics in the LOS from C. jejuni BD-07 and BD-39. Both BD-10 and BD-67 express the same LOS outer core, which appears to be a novel structure displaying GA2 and GD3 mimicry. Up to 90-100% of serum reactivity to gangliosides in two patients (DK-07 and DK-39) was inhibited by 50 µg/ml of LOS from the autologous C. jejuni isolates. However, patient DK-07 developed an anti-GD1a immune response while patient DK-39 developed an anti-GM1 immune response. CONCLUSION: Carbohydrate mimicry between C. jejuni LOS and gangliosides, and cross-reactive serum antibody precipitate the majority of GBS cases in Bangladesh.

Sialylation of Campylobacter jejuni lipo-oligosaccharides: impact on phagocytosis and cytokine production in mice.

BACKGROUND: Guillain-Barré syndrome (GBS) is a post-infectious polyradiculoneuropathy, frequently associated with antecedent Campylobacter jejuni (C. jejuni) infection. The presence of sialic acid on C. jejuni lipo-oligosaccharide (LOS) is considered a risk factor for development of GBS as it crucially determines the structural homology between LOS and gangliosides, explaining the induction of cross-reactive neurotoxic antibodies. Sialylated C. jejuni are recognised by TLR4 and sialoadhesin; however, the functional implications of these interactions in vivo are unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigated the effects of bacterial sialylation on phagocytosis and cytokine secretion by mouse myeloid cells in vitro and in vivo. Using fluorescently labelled GM1a/GD1a ganglioside-mimicking C. jejuni strains and corresponding (Cst-II-mutant) control strains lacking sialic acid, we show that sialylated C. jejuni was more efficiently phagocytosed in vitro by BM-MΦ, but not by BM-DC. In addition, LOS sialylation increased the production of IL-10, IL-6 and IFN-ß by both BM-MΦ and BM-DC. Subsequent in vivo experiments revealed that sialylation augmented the deposition of fluorescent bacteria in splenic DC, but not macrophages. In addition, sialylation significantly amplified the production of type I interferons, which was independent of pDC. CONCLUSIONS/SIGNIFICANCE: These results identify novel immune stimulatory effects of C. jejuni sialylation, which may be important in inducing cross-reactive humoral responses that cause GBS.

Campylobacter jejuni lipooligosaccharides modulate dendritic cell-mediated T cell polarization in a sialic acid linkage-dependent manner.

Carbohydrate mimicry between Campylobacter jejuni lipooligosaccharides (LOS) and host neural gangliosides plays a crucial role in the pathogenesis of Guillain-Barré syndrome (GBS). Campylobacter jejuni LOS may mimic various gangliosides, which affects the immunogenicity and the type of neurological deficits in GBS patients. Previous studies have shown the interaction of LOS with sialic acid-specific siglec receptors, although the functional consequences remain unknown. Cells that express high levels of siglecs include dendritic cells (DCs), which are crucial for initiation and differentiation of immune responses. We confirm that α2,3-sialylated GD1a/GM1a mimic and α2,8-sialylated GD1c mimic LOS structures interact with recombinant Sn and siglec-7, respectively. Although the linkage of the terminal sialic acid of LOS did not regulate expression of DC maturation markers, it displayed clear opposite expression levels of interleukin-12 (IL-12) and OX40L, molecules involved in DC-mediated Th cell differentiation. Accordingly, targeting DC-expressed siglec-7 with α2,8-linked sialylated LOS resulted in Th1 responses, whereas Th2 responses were induced by targeting with LOS containing α2,3-linked sialic acid. Thus, our data demonstrate for the first time that depending on the sialylated composition of Campylobacter jejuni LOS, specific Th differentiation programs are initiated, possibly through targeting of distinct DC-expressed siglecs.

TLR4-mediated sensing of Campylobacter jejuni by dendritic cells is determined by sialylation.

In Guillain-Barré syndrome (GBS), ganglioside mimicry of Campylobacter jejuni lipo-oligosaccharide (LOS) drives the production of cross-reactive Abs to peripheral nerve gangliosides. We determined whether sialic acid residues in C. jejuni LOS modulate dendritic cell (DC) activation and subsequent B cell proliferation as a possible mechanism for the aberrant humoral immune response in GBS. Highly purified sialylated LOS of C. jejuni isolates from three GBS patients induced human DC maturation and secretion of inflammatory cytokines that were inhibited by anti-TLR4 neutralizing Abs. The extent of TLR4 signaling and DC activation was greater with LOS of the wild type isolates than with nonsialylated LOS of the corresponding sialyltransferase gene knockout (cst-II mutant) strains, indicating that sialylation boosts the DC response to C. jejuni LOS. Supernatants of LOS-activated DCs induced B cell proliferation after cross-linking of surface Igs in the absence of T cells. Lower B cell proliferation indices were found with DC supernatants after DC stimulation with cst-II mutant or neuraminidase desialylated LOS. This study showed that sialylation of C. jejuni LOS enhances human DC activation and subsequent B cell proliferation, which may contribute to the development of cross-reactive anti-ganglioside Abs found in GBS patients following C. jejuni infection.

Effect of glucocorticoid receptor gene polymorphisms in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a postinfectious immune-mediated polyneuroradiculopathy in which host factors influence disease susceptibility and clinical course. Single-nucleotide polymorphisms (SNPs) in the glucocorticoid receptor (GR) gene influence the sensitivity to glucocorticoids and are related to both microbial colonization and susceptibility to develop auto-immune disease. This genetic variation may therefore also influence the chance to develop GBS. In this study, we genotyped 318 GBS patients and 210 control subjects for five known SNPs in the GR gene. We could distinguish six different GR haplotypes of which two carried the BclI polymorphism: haplotype 1, which consists of the minor allele of BclI in combination with the common variant of TthIIII and haplotype 2, which carries the minor allele of BclI as well as the minor allele of TthIIII. The GR haplotypes were not related to susceptibility to develop GBS. Carriers of haplotype 2 had more frequently preceding diarrhea, serum antibodies to GM1 and GD1a, and more severe muscle weakness at entry. Haplotype 1 carriers had a significantly better prognosis. In conclusion, GR haplotypes are not a susceptibility factor for GBS. However, haplotypes carrying the minor allele of the BclI polymorphism were related to the phenotype and outcome of GBS.

Susceptibility to Guillain-Barré syndrome is not associated with CD1A and CD1E gene polymorphisms.

Immune responses to microbial glycolipids that cross-react to neural epitopes may trigger the Guillain-Barré syndrome (GBS). CD1 molecules are involved in antigen presentation of glycolipids and variation in CD1 genes was recently reported to confer susceptibility to develop GBS. This hypothesis was tested by comparing single nucleotide polymorphisms (SNPs) of CD1A and CD1E in 312 well defined GBS patients and 212 healthy controls. SNPs in CD1A and CD1E were not associated with GBS susceptibility, specific clinical subgroups, anti-ganglioside antibodies, antecedent infections and prognosis. Based on this study, CD1 polymorphisms are not a susceptibility or disease modifying factor in GBS.

Subclass IgG to motor gangliosides related to infection and clinical course in Guillain-Barré syndrome.

In 176 patients with Guillain-Barré syndrome the subclass and cross-reactivity of serum IgG antibodies to motor gangliosides was related to preceding infections and clinical phenotypes. Two subgroups of patients were identified. Presence of only IgG1 antibodies was related to diarrhea, positive Campylobacter serology, cross-reactive antibodies to C. jejuni lipo-oligosaccharides and poor outcome. In contrast, having both IgG1 and IgG3 antibodies was related to upper respiratory tract infections, cross-reactive antibodies to Haemophilus influenzae lipo-oligosaccharides and better outcome. These findings support a model in which C. jejuni and H. influenzae infections induce two distinct patterns of cross-reactive antibodies with different clinical outcome.

Mannose-binding lectin genotypes and pre-eclampsia: a case-control study.

Both immunological and placental factors are involved in the pathogenesis of pre-eclampsia. The complement factor mannose-binding lectin (MBL) is associated with adverse pregnancy outcomes and has been suggested to play a role in abnormal placentation. We investigated whether MBL genotypes are associated with the systemic maternal syndrome pre-eclampsia. MBL2 gene polymorphisms were determined in a case-control study including 157 women with pre-eclampsia (case subjects) and 157 women with uncomplicated pregnancies (control subjects). Considering MBL polymorphisms, case and control subjects were categorized in groups of high (A), intermediate (B), and low (C) MBL production. No association was found between MBL genotypes and pre-eclampsia; adjusted odds ratios and 95% confidence intervals (95% CI) for group B were 0.97 (95% CI = 0.46-2.07) and for group C were 1.44 (95% CI = 0.52-3.94). A trend was found between MBL genotype groups B and C and severe pre-eclampsia or eclampsia. MBL genotypes were not found to be associated with pre-eclampsia; however low-MBL production genotypes might be considered as disease modifier. This suggests that MBL may play a role in modulating placental inflammation by facilitating clearance of apoptotic cells and cell debris.

Genetic polymorphisms of macrophage-mediators in Guillain-Barré syndrome.

Macrophages infiltrate peripheral nerves and may contribute to neural damage in the Guillain-Barré syndrome (GBS). We determined whether single nucleotide polymorphisms (SNP) in genes encoding macrophage-mediators are related to the susceptibility and severity of GBS. The frequencies of SNP in the TNFA, MMP9, IL10, and NOS2a genes did not differ between 263 GBS patients and 210 healthy subjects. The MMP9 C(-1562)T and TNFA C(-863)A SNP were associated with severe weakness and poor outcome, indicating that these SNP may be one of the factors predisposing to a severe form of GBS.

Mannose-binding lectin contributes to the severity of Guillain-Barré syndrome.

In Guillain-Barré syndrome (GBS), complement activation plays a crucial role in the induction and extent of the postinfectious immune-mediated peripheral nerve damage. Mannose-binding lectin (MBL) activates the complement system via the lectin pathway after recognition of repetitive sugar groups on pathogens. We investigated whether the MBL2 genotype, serum MBL level, and MBL complex activity are associated with the development and severity of GBS. Single nucleotide polymorphisms in the promoter region (-550 H/L and -221 X/Y) and exon 1 (A/O) of the MBL2 gene were determined in 271 GBS patients and 212 healthy controls. The frequencies of the H allele, HY promoter haplotype, and HYA haplotype, which are related to high MBL activity, were all increased in GBS patients compared with healthy controls (p < or = 0.03), particularly in severely affected GBS patients (MRC-sum score < 40) (p < or = 0.02). Severe weakness was also associated with high MBL concentrations and MBL complex activity in sera from GBS patients (p < 0.01). The MBL2 B allele was associated with functional deficiency and relatively mild weakness. These results support the hypothesis that complement activation mediated by MBL contributes to the extent of nerve damage in GBS, which is codetermined by the MBL2 haplotype.

Fas polymorphisms are associated with the presence of anti-ganglioside antibodies in Guillain-Barre syndrome.

Polymorphisms in genes involved in regulation of immune homeostasis may be a susceptibility factor in the induction of cross-reactive anti-ganglioside antibodies after infection in patients with Guillain-Barre syndrome (GBS). In this study we assessed whether polymorphisms in the promoter region of Fas and FasL and sFas and sFasL are related to GBS or its distinct clinical or serological subgroups. We show that the A(-670)G SNP in the promoter region of Fas and high levels of sFas are associated with the presence of anti-ganglioside antibodies, suggesting that Fas-FasL interaction is involved in the production of cross-reactive antibodies in GBS.

Mannosylated PLP(139-151) induces peptide-specific tolerance to experimental autoimmune encephalomyelitis.

SJL mice immunized with mannosylated (M-) PLP(139-151) in complete adjuvant do not develop EAE and little CNS mononuclear cell infiltration; other mannosylated peptides were ineffective in this experimental setting. Despite apparently normal T cell responses, M-PLP(139-151)-immunized mice show impaired delayed-type-sensitivity to PLP(139-151) but a normal response to other peptides. After re-immunization with PLP(139-151) in complete adjuvant, these mice are largely tolerant to EAE, show less T cell proliferation and decreased peptide-specific IgG2a. Our data suggest that M-PLP(139-151) induces peptide-specific tolerance to EAE via a mechanism of deletion or impaired migration of encephalitogenic T cells.